Canonical and Non-Canonical Notch Ligands

Abstract

Notch signaling induced by canonical Notch ligands is critical for normal embryonic development and tissue homeostasis through the regulation of a variety of cell fate decisions and cellular processes. Activation of Notch signaling is normally tightly controlled by direct interactions with ligand-expressing cells and dysregulated Notch signaling is associated with developmental abnormalities and cancer. While canonical Notch ligands are responsible for the majority of Notch signaling, a diverse group of structurally unrelated non-canonical ligands has also been identified that activate Notch and likely contribute to the pleiotropic effects of Notch signaling. Soluble forms of both canonical and non-canonical ligands have been isolated, some of which block Notch signaling and could serve as natural inhibitors of this pathway. Ligand activity can also be indirectly regulated by other signaling pathways at the level of ligand expression, serving to spatio-temporally compartmentalize Notch signaling activity and integrate Notch signaling into a molecular network that orchestrates developmental events. Here, we review the molecular mechanisms underlying the dual role of Notch ligands as activators and inhibitors of Notch signaling. Additionally, evidence that Notch ligands function independent of Notch are presented. We also discuss how ligand post-translational modification, endocytosis, proteolysis and spatio-temporal expression regulate their signaling activity.

Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility

“…In canonical Notch signaling, the NICD translocates to the nucleus and binds directly to RBP-Jκ, converting it from a transcriptional suppressor to an activator and inducing the transcription of downstream target genes (7). In contrast, noncanonical Notch signaling does not require activation of RBP-Jκ (6). In this study, the fact that the deletion of Rbpj completely rescues the phenotypes of N1ICD OEx mice indicates that the abnormalities that we observe when N1ICD is overexpressed are occurring through canonical pathway signaling.…”

“…It plays vital roles in cellular survival, communication, and differentiation throughout development from embryonic to adult life (5). Canonical Notch signaling is initiated after the interaction of Notch transmembrane receptors (Notch1-Notch4) with cell-bound ligands (δ-like 1, 3, or 4 or Jagged 1 or 2), which leads to a cleavage cascade of Notch involving ADAM proteases and γ-secretase (6). Subsequently, the cleaved Notch intracellular domain (NICD) translocates to the nucleus, where it interacts with transcriptional repressor Recombination Signal Binding Protein Jκ (RBP-Jκ; also known as CBF-1) and converts it into a transcriptional activator of downstream target genes, such as hairy enhancer of split and hairy enhancer of split-related transcription factor families (7,8).…”

Maternal and zygotic Zfp57 modulate NOTCH signaling in cardiac development

“…Alternatively, DLK1 may activate NOTCH signaling by recycling and/or presenting NOTCH receptor proteins for activation by canonical DSL ligands. It is also possible that DLK1 functions as a ligand for NOTCH1 and other NOTCH receptors within the same cells to activate NOTCH receptors through an autocrine mechanism (29). These hypotheses need to be tested in the future by investigating the specific interactions of DLK1 and NOTCH receptors.…”

“…ra, right atrium; rv, right ventricle; la, left atrium; lv, left ventricle; as, atrial septum; ct, cushion tissue; ASD, atrial septal defect (*); vs, ventricular septum; vm, ventricular myocardium. expressed in the endocardium and myocardium of Zfp57 A key activation event in NOTCH signaling is ligand-dependent γ-secretase-mediated cleavage of NOTCH receptors (5,6,11,(28)(29)(30). We performed immunostaining with a monoclonal antibody that can only detect the cleaved activated form of NOTCH1 receptor (N1ICD).…”

Human hepatic organoids for the analysis of human genetic diseases

“…JAG1 and CK7 were expressed at this time, and activated NOTCH1 (NICD) was present in the nucleus ( Figure 3D). Since the relative levels of cell surface expression of NOTCH receptors and their ligands on interacting cells affect cell fate determination (41), these changes in the pattern of JAG1 expression may play an important role in bile duct development during HO formation. It is noteworthy that changes in JAG1 expression are most pronounced in areas where cholangiocytes and bile ducts form.…”